2-thiomethylpyrimidin-4-yl-4-fluorophenylbenzil | 218162-50-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-thiomethylpyrimidin-4-yl-4-fluorophenylbenzil
• 英文别名: 1-(4-fluorophenyl)-2-(2-methylsulphanylpyrimidin-4-yl)-1,2-ethandione；1-(4-Fluorophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethane-1,2-dione
• CAS: 218162-50-6
• 化学式: C₁₃H₉FN₂O₂S
• 分子量: 276.291
• InChiKey: XONLIWTWNAWUMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  85.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-thiomethylpyrimidin-4-yl-4-fluorophenylbenzil 在 ammonium acetate 、 对甲苯磺酸 、 溶剂黄146 、 间氯过氧苯甲酸 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency

  摘要：

  Following the discovery of RPR200765, a series of pyrimidine analogues have been prepared as backups. Amongst them, RPR203494 was identified with a better in vitro profile than RPR200765A. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00034-8
• 作为产物：
  描述：

  4-甲基-2-甲硫基嘧啶 在 sodium hexamethyldisilazane 、 二甲基亚砜 作用下， 以 四氢呋喃 为溶剂， 反应 6.5h， 生成 2-thiomethylpyrimidin-4-yl-4-fluorophenylbenzil
  参考文献：
  名称：

  An Algorithm-Directed Two-Component Library Synthesized Via Solid-Phase Methodology Yielding Potent and Orally Bioavailable p38 MAP Kinase Inhibitors

  摘要：

  Previously we reported the identification of RPR200765A, a potent orally bioavailable pyridine-imidazole inhibitor of p38 mitogen-activated protein (MAP) kinase which suppressed paw swelling and joint pathology in streptococcal cell wall-induced arthritis. Herein, we report the use of solid-phase combinatorial organic synthesis for the parallel processing of a related pyrimidine-imidazole-based library with two points of structural variability. We report also that the application of a computer algorithm, the Monte Carlo Monomer Selection, maximized both the combinatorial synthetic efficiency and the bioavailability of the final compounds. In conjunction with the synthetic protocols, the polymer-supported quench technique was applied to the purification of the final compounds. Through rapid evaluation of the library using a p38 kinase assay and permeability assays, it was possible to identify a number of potent and orally bioavailable p38 MAP kinase inhibitors suitable for further biological investigation.

  DOI：

  10.1021/jm011132l

文献信息

• Imidazolyl-cyclic acetals
  申请人：Aventis Pharma Limited

  公开号：US06602877B1

  公开（公告）日：2003-08-05

  Compounds of formula (I) are described in which R1 is optionally substituted heteroaryl; R2 is optionally substituted aryl or optionally substituted heteroaryl; R3 is a group —L1—R7 or —L2—R8 [where L1 is an optionally substituted alkylene linkage; R7 is hydrogen, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, nitro, —S(O)nR9, —NHSO2R9, —C(═Z)OR10, —C(═Z)R10, —OR10, —N(R11)—C(═Z)R9, —NY1Y2, —SO2NY1Y2, —C(═Z)—NY1Y2, —N(R11)—C(═Z)—NY1Y2, —N(OR10)—C(═Z)—NY1Y2, —N(OR10)—C(═Z)R10, —C(═NOR10)R10, —C(═Z)NR10OR12, —N(R11)—C(═NR13)—NY1Y2 or —N(R11)—C(═Z)OR11; L2 is a direct bond or a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms and contains a double or triple carbon-carbon bond; and R8 is hydrogen, aryl, cycloalkenyl, cycloalkyl, heteroaryl or heterocycloalkyl]; R4 is a group —L3—R14 [where L3 is a direct bond or an optionally substituted alkylene linkage and R14 is hydrogen, alkyl, azido, hydroxy, alkoxy, aryl, arylalkyloxy, aryloxy, carboxy (or an acid bioisostere), cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, nitro, —NY4Y5, —N(R10)—C(═Z)—R15; —N(R10)—C(═Z)—L4—R16, —NH—C(═Z)—NH—R15, —NH—C(═Z)—NH—L4—R16, —N(R10)—SO2—R15, —N(R10)—SO2—L4—R16, —S(O)nR9, —C(═Z)—NY4Y5 or —C(═Z)—OR9]; R5 is hydrogen, alkyl or hydroxyalkyl; or R4 and R5, when attached to the same carbon atom, may form with the said carbon atom a cycloalkyl, cycloalkenyl or heterocycloalkyl ring or a group C═CH2; R6 is hydrogen or alkyl; and m is zero or an integer 1 or 2; and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (I) and N-oxides thereof, and their prodrugs. The compounds are TNF inhibitors and are useful as pharmaceuticals.

  式（I）的化合物描述如下：其中R1是可选择取代的杂环芳基；R2是可选择取代的芳基或可选择取代的杂环芳基；R3是一个基团—L1—R7或—L2—R8【其中L1是可选择取代的烷基链；R7是氢、芳基、氰基、环烷基、杂环芳基、杂环烷基、硝基、—S(O)nR9、—NHSO2R9、—C(═Z)OR10、—C(═Z)R10、—OR10、—N(R11)—C(═Z)R9、—NY1Y2、—SO2NY1Y2、—C(═Z)—NY1Y2、—N(R11)—C(═Z)—NY1Y2、—N(OR10)—C(═Z)—NY1Y2、—N(OR10)—C(═Z)R10、—C(═NOR10)R10、—C(═Z)NR10OR12、—N(R11)—C(═NR13)—NY1Y2或—N(R11)—C(═Z)OR11；L2是直接键或由2到约6个碳原子组成的直链或支链碳链，含有双键或三键碳-碳键；R8是氢、芳基、环烯基、环烷基、杂环芳基或杂环烷基】；R4是一个基团—L3—R14【其中L3是直接键或可选择取代的烷基链，R14是氢、烷基、叠氮基、羟基、烷氧基、芳基、芳基烷氧基、芳氧基、羧基（或酸生物等构异体）、环烷氧基、杂环芳基、杂环芳基烷氧基、杂环芳氧基、杂环烷基、杂环烷氧基、硝基、—NY4Y5、—N(R10)—C(═Z)—R15；—N(R10)—C(═Z)—L4—R16、—NH—C(═Z)—NH—R15、—NH—C(═Z)—NH—L4—R16、—N(R10)—SO2—R15、—N(R10)—SO2—L4—R16、—S(O)nR9、—C(═Z)—NY4Y5或—C(═Z)—OR9】；R5是氢、烷基或羟基烷基；或者R4和R5，当连接到同一碳原子时，可以与所述碳原子形成环烷基、环烯基或杂环烷基环或基团C═CH2；R6是氢或烷基；m为零或整数1或2；以及其N-氧化物，以及它们的前药；以及式（I）的化合物及其N-氧化物的药学上可接受的盐和溶剂（例如水合物），以及它们的前药。这些化合物是肿瘤坏死因子抑制剂，可用作药物。
• Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38α mitogen-activated protein kinase
  作者：Dae-Kee Kim、Jin-Hwi Lim、Jung A. Lee、Purushottam M. Dewang

  DOI：10.1016/j.bmcl.2008.06.007

  日期：2008.7

  A series of trisubstituted imidazole derivatives containing a 4-fluorophenyl group, a pyrimidine ring, and a CN- or CONH(2)-substituted benzyl moiety have been synthesized and evaluated for p38 alpha MAP kinase inhibitory activity. Among them, compounds 22c, 27b, and 28b inhibited p38 alpha MAP kinase with IC(50) values 27.6, 28, and 31 nM, respectively. (c) 2008 Elsevier Ltd. All rights reserved.
• Synthesis and structure–activity relationships of 4-fluorophenyl-imidazole p38α MAPK, CK1δ and JAK2 kinase inhibitors
  作者：Jean-Paul G. Seerden、Gabriela Leusink-Ionescu、Titia Woudenberg-Vrenken、Bas Dros、Grietje Molema、Jan A.A.M. Kamps、Richard M. Kellogg

  DOI：10.1016/j.bmcl.2014.05.080

  日期：2014.8

  The synthesis and structure-activity relationships of novel 4-(4 '-fluorophenyl)imidazoles as selective p38 alpha MAPK, CK1 delta and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38 alpha MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1 delta inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. (C) 2014 Elsevier Ltd. All rights reserved.
• IMIDAZOLYL-CYCLIC ACETALS
  申请人：RHONE-POULENC RORER LIMITED

  公开号：EP0988301A1

  公开（公告）日：2000-03-29
• US6602877B1
  申请人：——

  公开号：US6602877B1

  公开（公告）日：2003-08-05